Flumethasone, 6xcex1,9xcex1-difluoro-16xcex1-methylprednisolone was described for the first time in 1962. Although this corticosteroid has an enhanced antiinflammatory activity its clinical application has not been widely used.
At the present time, its economical preparation on an industrial scale is ever more important because it is also an excellent starting material for the production of new difluoro-17-carboxyl androstenes, which are becoming increasingly important from a clinical point of view.
Flumethasone was patented for the first time in U.S. Pat. No. 3,499,016 (1962) as well as, among other patents, British Patent 902,292 (1970).
The new synthetic techniques developed since 1970 naturally permit a more efficient production of flumethasone with considerably increased yields compared to those obtained with the initial patents.
The present invention relates to a new process for the preparation of flumethasone as well as to the preparation of 6xcex1,9xcex1-difluoro-11xcex2, 17xcex1-dihydroxy-16xcex1-methyl-17xcex2-carboxy-androsta-1,4-diene-3-one which is also called xe2x80x9chydroxyacidxe2x80x9d, an excellent starting material for the production of fluticasone and other new antiinflammatory compounds of the androsta-1, 4-diene series. The xe2x80x9chydroxyacidxe2x80x9d was first described and claimed in U.S. Pat. No. 3,636,010 (priority 1968).
The European Patent 0 610 138 B1 (1994) describes a new synthetic route for the preparation of the so called xe2x80x9chydroxyacidxe2x80x9d. However, the present invention represents considerable unexpected advantages in relation to this prior process patent, namely:
the reaction sequence is reduced by one reaction step and by the elimination of the desolvatation step of 6xcex1,9xcex1-difluoro-11xcex2,17xcex1-dihydroxy 16xcex1-methyl 17xcex2-methoxycarbonyl androsta-1,4-diene-3-one, an additional production step,
the present process avoids the use of a highly toxic reagent, dimethyl sulphate,
permits the simultaneous deacetylation and degradative oxidation of the pregnane side chain forming directly the equivalent androstan derivative,
increased yield of the hydroxyacid with excellent purity.
Whilst all the reaction steps of the present invention are realised in the pregnane series excepting the last one thus permitting an efficient preparation of flumethasone, the reaction sequence of EP 0 610 138 B1 transforms the common starting material of both processes as from the first step into the androstane series.
According to the present invention the preparation of flumethasone and its 17xcex2-carboxyl androsten analogue follows the following steps:
a) the starting material of the formula: 
is reacted with benzoyl chloride so as to obtain the new compound with the following formula: 
b) the benzoate of the formula III a) is then reacted with an electrophilic fluorination agent so as to introduce fluorine in the position C6 yielding the new compound of the formula: 
c) which yields, after eliminating the protection in C3, a compound of the formula: 
d) thereafter the compound IV is reacted with hydrofluoric acid yielding flumethasone 21-acetate of the formula: 
in which R is a residue of acetic acid, that is 6xcex1,9xcex1-difluoro-11xcex2,17xcex1, 21-trihydroxy-16xcex1-methyl-pregna-1,4-diene-3,20-dione,21-acetate;
e1) followed by the hydrolisation of this compound with methanolic potassium hydroxide yielding flumethasone free alcohol, in which R is hydrogen;
e2) alternatively, flumethasone acetate is reacted with methanolic potassium hydroxide and hydrogen peroxide solution yielding the desired compound, so called xe2x80x9chydroxyacidxe2x80x9d of the formula: 
The present invention permits the direct transformation of flumethasone acetate into compound I.
The compounds III a) and III b) are new.
The compound I can also be obtained as described in U.S. Pat. No. 3,636,010 by oxidizing flumethasone free alcohol.
The starting material of the present process is commercially available and widely used in the preparation of corticosteroids such as dexamethasone and icomethasone.
So as to introduce fluorine in C6 with an electrophilic fluorination agent it is necessary to activate first the position C6. For that purpose the 3-ceto group is enolised by carboxylic acid chloride forming an enolic ester residue of the formula xe2x80x94COR in which R is an aryl or aralkyl group. The preferred compound for the enolisation is benzoyl chloride yielding the compound of formula III a) in the presence of a tertiary amine, like pyridine. The preferred solvent is N,Nxe2x80x2-dimethylacetamide and the reaction is realised at a temperature of 80 to 85xc2x0 C., yielding the xcex943,5 enol benzoate. Thereafter the compound III a) is reacted with an electrophilic fluorination agent to yield the corresponding 6 fluoro derivative. The preferred fluorination agent is the 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate), Selectfluor(copyright). So as to realise the fluorination at C6, the preferred solvent is acetonitrile in presence of water at a temperature of xe2x88x925xc2x0 C.xc2x12xc2x0 C. After the C6 fluorination the 3 enolic ester could be easily transformed into the system of 3-ceto-1,4-diene yielding the compound IV. The elimination of the enolic ester is realised by an aqueous solution of sodium metabisulfite and ammonia.
In the next step a 9,11-epoxy group of compound IV is reacted with a concentrated aqueous solution of hydrofluoric acid or with a solution of hydrogen fluoride in N,Nxe2x80x2-dimethylformamide by per se known processes at a temperature inferior to 25xc2x0 C. When compound IV is practically completely reacted, the reaction mixture is poured into a mixture of ice and ammonia sufficient to neutralise the hydrofluoric acid and precipitate simultaneously the flumethasone 21-acetate with a high yield and purity. Of course the product obtained can be recrystallized for instance from methanol. Also the 21-acetate obtained can be subsequently hydrolized by any of the known processes yielding flumethasone free alcohol. One of the preferred processes is realised in degassed methanolic potassium hydroxide at a temperature comprised between xe2x88x9215xc2x0 C. and xe2x88x925xc2x0 C. End of the reaction is ascertained by HPLC after one hour and it is considered complete when the amount of starting compound is inferior to 1%.
In order to realise the degradative oxidation, according to prior art, flumethasone is suspended in tetrahydrofuran and a solution of the oxidation agent is added dropwise. The substrate first starts to dissolve followed by precipitation. The oxidation is performed preferably at 20xc2x0 C. employing, for example, periodic acid. After one hour of stirring, completion of the reaction is controlled by HPLC. Once the amount of non-reacted flumethasone is inferior to 0.3%, the reaction is considered complete. Subsequently, the reaction mixture containing compound I is precipitated by adding to an aqueous solution of sodium metabisulfite and ice.
According to the present invention one can deacetylate and oxidise simultaneously flumethasone 21-acetate by methanolic potassium hydroxide and aqueous hydrogen peroxide yielding, after completion of the reaction, the desired hydroxyacid, compound I, by acidifying the reaction mixture with diluted hydrochloric acid until pH 2. This reaction is performed at 10xc2x0 C., xc2x12xc2x0 C. with agitation until the reaction is complete.
The cumulative stoichiometric yield of the process described in EP 0 610 138 B1 so as to obtain unrecrystallized compound I is 48.9% as from 9,11xcex2-epoxy-17xcex1,21-dihydroxy-pregna-1,4-diene-3,20-dione, whilst according to the present process the cumulative stoichiometric yield obtained is 62.4%, as per examples 1 b), 2 and 4, as from the 21-acetate of the above starting material. So as to obtain a valid comparison of yields, the starting material of EP 0 610 138 B1 has been first acetylated with a yield of 110% w/w and the cumulative stoichiometric yield was calculated on basis of this value and of examples 1 b), 2 and 4, resulting in 61.7%.